rs1406229

Variant names:

• chr2-29358896-C-T
• rs1406229
• NM_004304.5:c.1282+24836G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004304.5(ALK):​c.1282+24836G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,112 control chromosomes in the GnomAD database, including 2,136 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2136 hom., cov: 32)
• Consequence: ALK NM_004304.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0290
• Publications: 3 publications found

Genes affected

ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]

ALK Gene-Disease associations (from GenCC):

• neuroblastoma, susceptibility to, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1282+24836G>A		intron_variant	Intron 5 of 28	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2209+24836G>A		intron_variant	Intron 5 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1282+24836G>A		intron_variant	Intron 5 of 28	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.151+24836G>A		intron_variant	Intron 4 of 27	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23020 AN: 151994 Hom.: 2134 Cov.: 32

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.172

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.151 AC: 23021 AN: 152112 Hom.: 2136 Cov.: 32 AF XY: 0.149 AC XY: 11061 AN XY: 74360

African (AFR) AF: 0.0636 AC: 2639 AN: 41504

American (AMR) AF: 0.130 AC: 1982 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 894 AN: 3468

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5188

South Asian (SAS) AF: 0.245 AC: 1181 AN: 4814

European-Finnish (FIN) AF: 0.151 AC: 1597 AN: 10562

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14000 AN: 67976

Other (OTH) AF: 0.170 AC: 359 AN: 2114

Alfa AF: 0.181 Hom.: 329

Bravo AF: 0.141

Asia WGS AF: 0.108 AC: 376 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.65
PhyloP100		0.029
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1406229; hg19: chr2-29581762;